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The role of tissue-type plasminogen activator A-chain domains in plasma clearance

Fibrinolysis and Proteolysis
Publication Date
DOI: 10.1016/0268-9499(89)90048-9
  • T-Pa Domains
  • T-Pa Muteins
  • Clearance Determinant(S)
  • Biology


Abstract The fibrinolytic enzyme tissue-type plasminogen activator (t-PA) exhibits a short plasma half-life in vivo. We have used a series of modified t-PA species to investigate the role of the A-chain domains, i.e. finger (F), growth factor (G) and kringles (K 1 and K 2), in clearance. We have previously established that removal of F had no effect on clearance whereas removal of G retarded clearance. The study has now been extended by using a new group of t-PA species, namely FG-K 2B, FGK 1-B, F--K 2B, ---K 2B and F-K 2K 2B. The proteins were expressed in a Hela cell transient system and were extensively purified. The active centre of each mutein was reversibly acylated with 4′ amidinophenyl-N, N-dimethyl-4-aminobenzoate and the clearance rate determined in a guinea pig model. FGK 1-B was cleared at the same rate as native t-PA suggesting that K2 is not involved in clearance. FG-K 2B, F-K 2B, F-K 2K 2B and --- K 2B were all relatively slowly cleared, at a rate similar to that previously described for F-K 1K 2B. Our results show that deletion of multiple domains had no more effect on clearance than deletion of G or K 1 alone. It seems likely that one, or possibly more, clearance determinants are associated with the G and/or K 1 domains. Studies on the isolated B-chain suggest that this too might carry a clearance determinant.

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